Escape rates in periodically driven Markov processes

We present an approximate analytical expression for the escape rate of time-dependent driven stochastic processes with an absorbing boundary such as the driven leaky integrate-and-fire model for neural spiking. The novel approximation is based on a discrete state Markovian modeling of the full long-time dynamics with time-dependent rates. It is valid in a wide parameter regime beyond the restraining limits of weak driving (linear response) and/or weak noise. The scheme is carefully tested and yields excellent agreement with three different numerical methods based on the Langevin equation, the Fokker-Planck equation and an integral equation.Comment: 10 pages, 5 figure

Aviation System Analysis Capability Executive Assistant Design

In this technical document, we describe the design developed for the Aviation System Analysis Capability (ASAC) Executive Assistant (EA) Proof of Concept (POC). We describe the genesis and role of the ASAC system, discuss the objectives of the ASAC system and provide an overview of components and models within the ASAC system, and describe the design process and the results of the ASAC EA POC system design. We also describe the evaluation process and results for applicable COTS software. The document has six chapters, a bibliography, three appendices and one attachment

Conceptual design analysis for a two-stage-to-orbit semi-reusable launch system for small satellites

This paper presents the conceptual design and performance analysis of a partially reusable space launch vehicle for small payloads. The system employs a multi-stage vehicle powered by rocket engines, with a reusable first stage capable of glided or powered flight, and expendable upper stage(s) to inject 500 kg of payload into low Earth orbits. The space access vehicle is designed to be air-launched from a modified aircraft carrier. The aim of the system design is to develop a commercially viable launch system for near-term operation, thus emphasis is placed on the efficient use of high TRL technologies and on the commercial potential of the technical design. The vehicle design is analysed using a multi-disciplinary design optimisation approach to evaluate the performance, operational capabilities and design trade-offs. Results from two trade-off studies are shown, evaluating the choice wing area and thus aerodynamic characteristics, and the choice of stage masses and engines selection on the mission performance

Vehicle and mission design of a future small payload launcher

This paper presents the conceptual design and performance analysis of a partially reusable space launch vehicle for small payloads. The system uses a multi-stage vehicle with rocket engines, with a reusable first stage capable of glided or powered flight, and expendable upper stage(s) to inject a 500 kg payload in different low Earth orbits. The space access vehicle is designed to be air-launched from a modified aircraft carrier. The aim of the system design is to develop a commercially viable launch system for near-term operation, thus emphasis is placed on the efficient use of high TRL technologies. The vehicle design are analysed using a multi-disciplinary design optimisation approach to evaluate the performance, operational capabilities and design trade-offs

Herpes Simplex Virus-1 Infection in Human Primary Corneal Epithelial Cells is Blocked by a Stapled Peptide that Targets Processive DNA Synthesis

Purpose: Acyclovir is most commonly used for treating ocular Herpes Keratitis, a leading cause of infectious blindness. However, emerging resistance to Acyclovir resulting from mutations in the thymidine kinase gene of Herpes Simplex Virus −1 (HSV-1), has prompted the need for new therapeutics directed against a different viral protein. One novel target is the HSV-1 Processivity Factor which is essential for tethering HSV-1 Polymerase to the viral genome to enable long-chain DNA synthesis. Methods: A series of peptides, based on the crystal structure of the C-terminus of HSV-1 Polymerase, were constructed with hydrocarbon staples to retain their alpha-helical conformation. The stapled peptides were tested for blocking both HSV-1 DNA synthesis and infection. The most effective peptide was further optimized by replacing its negative N-terminus with two hydrophobic valine residues. This di-valine stapled peptide was tested for inhibiting HSV-1 infection of human primary corneal epithelial cells. Results: The stapled peptides blocked HSV-1 DNA synthesis and HSV-1 infection. The unstapled control peptide had no inhibitory effects. Specificity of the stapled peptides was confirmed by their inabilities to block infection by an unrelated virus. Significantly, the optimized di-valine stapled peptide effectively blocked HSV-1 infection in human primary corneal epithelial cells with selectivity index of 11.6. Conclusions: Hydrocarbon stapled peptides that simulate the α-helix from the C-terminus of HSV-1 DNA polymerase can specifically block DNA synthesis and infection of HSV-1 in human primary corneal epithelial cells. These stapled peptides provide a foundation for developing a topical therapeutic for treating human ocular Herpes Keratitis. © 202

A commercially driven design approach to UK future small payload launch systems

Miniaturisation of satellite componentry, increasingly capable small sensors and substantial increases in processing capacity and transmission bandwidth are driving rapid growth in small payload development and consequential launch demand. The advent of horizontal take-off spaceports opens the door for a new generation of small payload launch systems that will fulfil this demand. However, the key to a launch system's success is its ability to provide a return on the substantial costs of development while delivering pricing levels commensurate with the needs of launch customers. Therefore, commercially led design approaches are needed to refine and optimise the design of the new small payload launch systems required. This approach was embodied in an ongoing UKSA funded NSTP2 project titled Future UK Small Payload Launcher (FSPLUK). The approach is first founded upon a bespoke and specific market assessment. This characterises, segments and quantifies the commercial opportunity and establishes principal desired system performance requirements. An assessment of available technologies at differing TRLs permits initial vehicle configuration options to be developed and technically assessed. Technically viable options are then assessed in terms of commercial viability with the best advanced into more detailed technical assessment and system optimisation. The resultant vehicles are again tested for commercial viability and, if successful, emerge as recommended development avenues. Using these methods, it has been possible to iterate design concepts from apparently simple yet economically sub-optimised stacked launcher systems through several design iterations to a resultant highly flexible and economically efficient conceptual design. The key finding relates to the inter-relationship between payload flexibility, in permitting maximised flight rates from a reasonably complex but highly reusable first stage design, and low disposable upper stage unit cost. This has driven the resultant system to feature an air launched integrated re-usable first stage vehicle, configured with a flexible internal payload bay from which one or more upper stages are deployed. This configuration maximises commercial utility and reusability. The resultant high flight rate allows development costs to be efficiently amortised with minimised direct launch costs. The configuration therefore meets low cost per kg price targets while delivering a positive return on development expenditure over life. It also provides a flight proven vehicle platform with available internal real-estate for application as a hypersonic air test platform for new propulsion systems, such as SABRE. The commercially led approach has created the foundation for viable and economically justifiable development

How to launch small payloads? Evaluation of current and future small payload launch systems

This paper describes a preferable vehicle classification alongside a brief description of key technologies available on the shelf or under development to address the demand of the small payload market. This is followed by a discussion on the investigation of the current market and the future forecast; regarding the delivery of small payloads into orbit

MEK blockade converts AML differentiating response to retinoids into extensive apoptosis

: The aberrant function of transcription factors and/or kinase-based signaling pathways that regulate the ability of hematopoietic cells to proliferate, differentiate, and escape apoptosis accounts for the leukemic transformation of myeloid progenitors. Here, we demonstrate that simultaneous retinoid receptor ligation and blockade of the MEK/ERK signaling module, using the small-molecule inhibitor CI-1040, result in a strikingly synergistic induction of apoptosis in both acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) cells with constitutive ERK activation. This proapoptotic synergism requires functional RAR and RXR retinoid receptors, as demonstrated using RAR- and RXR-selective ligands and RAR-defective cells. In the presence of MEK inhibitors, however, retinoid-induced chromatin remodeling, target-gene transcription, and granulocytic differentiation are strikingly inhibited and apoptosis induction becomes independent of death-inducing ligand/receptor pairs; this suggests that apoptosis induction by combined retinoids and MEK inhibitors is entirely distinct from the classical "postmaturation" apoptosis induced by retinoids alone. Finally, we identify disruption of Bcl-2-dependent mitochondrial homeostasis as a possible point of convergence for the proapoptotic synergism observed with retinoids and MEK inhibitors. Taken together, these results indicate that combined retinoid treatment and MEK blockade exert powerful antileukemic effects and could be developed into a novel therapeutic strategy for both AML and APL